Microneedle patches and methods

ABSTRACT

Microneedle patches and systems, and methods for use of such patches and systems. In one aspect, a microneedle patch is provided including a tab portion for handling the microneedle patch. In another aspect, a system is provided including a microneedle patch and a tray for housing the microneedle patch. In still another aspect, various indicators providing for providing feedback prior to, during, and after administration of the microneedle patch are provided. Advantageously, the described microneedle patches and systems provide improved handling and ease of application of the microneedle patches to skin for the delivery of therapeutic agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 16/384,665, filedApr. 15, 2019, which is a continuation of U.S. application Ser. No.15/025,683, filed Mar. 29, 2016, which is a national stage ofPCT/US14/58406, filed Sep. 30, 2014, which claims priority to U.S.Provisional Application No. 61/884,396, filed Sep. 30, 2013, to U.S.Provisional Application No. 62/024,062, filed Jul. 14, 2014, and to U.S.Provisional Application No. 62/029,202, filed Jul. 25, 2014. All ofthese prior applications are incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under Contract No.EB012495 awarded by the National Institutes of Health. The Governmenthas certain rights in the invention.

BACKGROUND

The present application is generally in the field of microneedle patchesfor the transport of therapeutic or biological molecules into the skinor across tissue barriers.

Transdermal drug delivery provides several advantages over other routesfor administering a drug formulation to a patient. One method fortransdermal drug delivery involves using microneedle arrays to bypassthe barrier properties of the stratum corneum. Although microneedlearrays were first reported over 15 years ago, numerous obstacles haveprolonged the development of microneedle arrays and delayed itscommercialization. For example, the small size of the microneedles makesverifying effective administration of the therapeutic agents difficult.Many groups have looked to use of applicators and other types of specialinsertion devices that are used to apply a pre-set force that willensure that the microneedles penetrate the stratum corneum. Theseapplicators and other insertion devices, however, can be cumbersome touse and unnecessarily increase the cost of using the microneedle arrays.

For example, most microneedle systems under development either haveseparate, complex applicators or integrated applicators. The separate,complex applicators are used to handle and apply microneedle patches tothe patients and can be burdensome to the user, bulky, costly for singleuse applications, and/or non-ideal for multi-person administration(e.g., mass vaccinations) due to cross-contamination issues. Theintegrated applicators are integrated into the microneedle devicesthemselves and become wearable systems that must be worn for theduration of the required wear time, which adds an undesirable level of3-dimensionality to a wearable patch/device.

Other problems that have been difficult to overcome have included thescale-up of consistent and reliable methods of manufacture ofmicroneedle arrays, development of highly concentrated and stabletherapeutic agents that can be effectively administered usingmicroneedle arrays, and cost effective systems for protecting themicroneedles after manufacture until their use.

Thus, there remains a need for simple, effective, and economicallydesirable devices for transdermal administration of a variety of drugtypes to a patient.

SUMMARY

Improved microneedle patches and systems, and methods of use thereofhave been developed which address one or more of the above-describedneeds.

In one aspect, a microneedle patch for administration of an activepharmaceutical ingredient (API) or other substance of interest into abiological tissue is provided. For example, the biological tissue may bethe skin or a mucosal tissue of a human or other mammal in need oftreatment or prophylaxis. The patch includes a base substrate having amicroneedle side and an opposing back side with one or more solidmicroneedles extending from the microneedle side of the base substrate,the one or more solid microneedles including a substance of interest,such as an API. The patch further includes an adhesive layer and ahandle layer affixed to the back side of the base substrate, the handlelayer including a tab portion which extends away (e.g., laterally) fromthe one or more solid microneedles and permits a person to manually holdthe tab portion (e.g., between a thumb and finger) to manipulate thepatch without contacting the one or more solid microneedles.

In another aspect, a system for storing and transporting one or moremicroneedle patches is provided. The system includes one or moremicroneedle patches and a tray with an upper surface region surroundingone or more recessed regions. Each of the one or more recessed regionsis dimensioned to receive in a non-contacting manner the one or moresolid microneedles of a corresponding microneedle patch, with a portionof the adhesive layer of the microneedle patch being releasably securedto the upper surface region of the tray.

In yet another aspect, a microneedle patch for administration of an APIor other substance of interest into a patient's skin (or into anotherbiological tissue) including one or more feedback indicators isprovided. The patch includes a base substrate having a microneedle sideand an opposing back side with one or more solid microneedles extendingfrom the microneedle side of the base substrate, wherein the one or moremicroneedles include the substance of interest, for example as part ofthe microneedle structure and/or as a coating on the microneedlestructure.

In one embodiment, the microneedle patch includes a mechanical forceindicator configured to provide an audible, tactile, and/or visualsignal when a force applied to the patch by a user, in the course ofapplying the patch to a patient's skin (or into another biologicaltissue) to insert the one or more microneedles therein, meets or exceedsa predetermined threshold. The mechanical force indicator may be in linewith and generally centered about the microneedles on the opposing backside of the base substrate.

In another embodiment, the one or more solid microneedles aredissolvable microneedles and the patch includes an indicator forproviding an audible, tactile, or visual signal indicative of the one ormore microneedles puncturing a patient's skin and/or completion ofdelivery of the substance of interest from the one or more solidmicroneedles in vivo following application of the patch to a patient'sskin.

Methods for administering an API or other substance of interest to apatient with a microneedle patch are also provided. The methods includeremoving the microneedle patch from a tray in which the microneedlepatch is releasably secured by manually grasping a tab portion of themicroneedle patch, e.g., between the thumb and finger; applying themicroneedle patch to a patient's skin; manually pressing the microneedlepatch, e.g., with a finger, thumb, or heel of hand, to apply a pressuresufficient to insert the one or more microneedles into the patient'sskin, and removing the microneedle patch from the patient's skin bygrasping the tab portion of the microneedle patch between the thumb andfinger. Similar steps could also be used to apply the patch to abiological tissue other than the skin.

Additional aspects will be set forth in part in the description whichfollows, and in part will be obvious from the description, or may belearned by practice of the aspects described below. The advantagesdescribed below will be realized and attained by means of the elementsand combinations particularly pointed out in the appended claims. It isto be understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B, and 1C are cross-sectional views of microneedle patchesand systems according to some embodiments of the present disclosure.

FIG. 2A is an exploded, perspective view, and FIG. 2B is an assembledperspective view, of a microneedle patch in accordance with oneembodiment of the present disclosure.

FIG. 3A is an exploded, perspective view, and FIG. 3B is an assembledperspective view, of a microneedle system in accordance with oneembodiment of the present disclosure.

FIG. 4A is an exploded, perspective view, and FIG. 4B is an assembledperspective view, of a microneedle system in accordance with anotherembodiment of the present disclosure.

FIG. 5A is an exploded, perspective view, and FIG. 5B is an assembledperspective view, of a microneedle system in accordance with stillanother embodiment of the present disclosure.

FIG. 6A is an exploded perspective view, and FIG. 6B is an assembledperspective view, of a mechanical force indicator in accordance with oneembodiment of the present disclosure. FIG. 6C is a perspective, top viewof the mechanical force indicator affixed to a microneedle patch inaccordance with one embodiment of the present disclosure.

FIGS. 7-12C are schematics illustrating the operation and use of variousfeedback indicators associated with a microneedle patch, in accordancewith several different embodiments of the present disclosure.

FIGS. 13A-D are schematics illustrating a process for using amicroneedle system in accordance with one embodiment of the presentdisclosure of administering a microneedle patch to a patient.

FIG. 14A is a partial cross-sectional view of an uncoated microneedle.FIG. 14B is a partial cross-sectional view of a coated microneedle.

DETAILED DESCRIPTION

Improved microneedle patches and systems have been developed. Inembodiments, the systems provide a microneedle patch which is simpler indesign and ease of use. The systems provide improved handling and easeof application of the microneedle patches, e.g., to the skin of apatient, in a way that insures the proper microneedle insertion withoutresort to complex applicator systems.

Unless otherwise defined herein or below in the remainder of thespecification, all technical and scientific terms used herein havemeanings commonly understood by those of ordinary skill in the art towhich the present invention belongs. It is also to be understood thatthe terminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting. In describing andclaiming the present invention, the following terminology will be usedin accordance with the definitions set out below.

As used in this specification and the appended claims, the singularforms “a”, “an,” and “the” include plural referents unless the contentclearly dictates otherwise. Thus, for example, reference to “acomponent” can include a combination of two or more components;reference to “a buffer” can include mixtures of buffers, and the like.

The term “about”, as used herein, indicates the value of a givenquantity can include quantities ranging within 10% of the stated value,or optionally within 5% of the value, or in some embodiments within 1%of the value.

Embodiments of the present application include microneedle patches andsystems having features to improve handling and use of the microneedlepatches. Generally described, microneedle patches include a basesubstrate with one or more microneedles extending from the basesubstrate. In a preferred embodiment, the microneedle patch includes anarray of several microneedles, e.g., from 10 to 1000 microneedles. In apreferred embodiment, the microneedles are solid microneedles thatinclude a substance of interest, such as an active pharmaceuticalingredient (API), which becomes solubilized in vivo following insertionof the microneedle into a biological tissue, e.g., into the skin of apatient. For example, the substance of interest may be mixed into awater soluble matrix material forming the solid microneedle 1410extending from a base substrate 1400 (FIG. 14A), or the substance ofinterest may in the form of a coating 1430 on a microneedlesub-structure 1420 extending from a base substrate 1400 (FIG. 14B). Ineither case, the substance of interest is provided in a formulationreferred to herein as being “dissolvable.” In embodiments in which thesubstance of interest and a matrix material in which the substance ofinterest is dispersed form the structure of the microneedle, the matrixmaterial also preferably is dissolvable in vivo, such that the entireportion of the microneedle inserted into the biological tissue dissolvesin vivo (e.g., about 90 to about 95% of the total length of themicroneedle). In embodiments in which the substance of interest is partof a coating on a microneedle substructure, the substructure may also bedissolvable in vivo, but it is not required.

In embodiments, the one or more microneedles have a height from about100 μm to about 2000 μm, from about 100 μm to about 1500 μm, from about100 μm to about 1000 μm, or from about 500 μm to about 1000 μ. The oneor more microneedles may be arranged on a base substrate in any suitabledensity. For example, a plurality of microneedles may be arranged ineven or staggered rows in an array, wherein each microneedle isseparated from its nearest neighboring microneedle by a distance betweenabout 50% and about 200% of the height of the microneedle, (e.g.,between about 75% about and about 150% of the height of the microneedle,or by about equal to the height of the microneedle). Any suitable numberof microneedles may be used. In one embodiment, a plurality ofmicroneedles may include from 5 to 10,000 microneedles, such as from 50to 1000 microneedles or from 50 to 200 microneedles.

Microneedle Patches

An exemplary microneedle patch with a plurality of solid microneedles isillustrated in FIG. 1A. The patch 100 includes a base substrate 116 witha plurality of microneedles 114. The plurality of microneedles 114 maybe affixed to a backing layer 110 by an adhesive layer 118 disposedbetween the backing layer 110 and the back side of the base substrate116. In some embodiments, the backing layer 110 may include a tabportion 112 which extends away from the plurality of microneedles 114.Alternatively, the tab portion may be disposed in a separate layer (notshown). Thus, the tab portion may be in the same plane or a differentplane than the backing layer. For example, in FIG. 1A the tab portion112 extends laterally away from the plurality of microneedles 114. The“backing layer” and “handle layer” may be used interchangeably in thepresent disclosure unless expressly provided otherwise.

The tab portion 112 advantageously enables a patient or caregiver tohandle the patch without contacting the “body portion” of the patchdefined by the base substrate 116 and plurality of microneedles 114,thereby beneficially reducing the potential of contaminating or damagingthe plurality of microneedles 114 and eliminating unwanted contact withthe adhesive layer. For example, the tab portion 112 may be sized andshaped to permit a person to manually hold the tab portion 112 (e.g.,between a thumb and finger). Although the tab portion 112 is illustratedin FIG. 1A as extending laterally asymmetrically from the body portion,other shapes and sizes also are envisioned. For example, the tab portionmay be about the same size as the body portion, larger than the bodyportion, or smaller than the body portion. In some embodiments, the tabportion may extend laterally from all sides of the body portion. Thesize of the tab portion may be at least in part dictated by the materialused to make the tab portion (e.g., depending on its stiffness and thelike).

The backing layer may be made out of a variety of materials, and may bethe same or different than the tab portion. In some embodiments, thebacking layer may be a composite material or multilayer materialincluding materials with various properties to provide the desiredproperties and functions. For example, the backing material may beflexible, semi-rigid, or rigid, depending on the particular application.As another example, the backing layer may be substantially impermeable,protecting the one or more microneedles (or other components) frommoisture, gases, and contaminants. Alternatively, the backing layer mayhave other degrees of permeability and/or porosity based on the desiredlevel of protection that is desired. Non-limiting examples of materialsthat may be used for the backing layer include various polymers,elastomers, foams, paper-based materials, foil-based materials,metallized films, and non-woven and woven materials.

The backing layer 110 may be temporarily or permanently affixed to thebase substrate 116 by the adhesive layer 118. In some embodiments, theadhesive layer may be disposed primarily in the body portion of thepatch between the base substrate 116 and backing layer 110. For example,the adhesive layer 118 may be disposed between the base substrate 116and backing layer 110, and may extend beyond the base substrate 116 tohelp adhere the patch to the patient's skin during application. Theportion of the adhesive layer extending beyond the base substrate alsomay function to adhere the patch to a tray or container covering theplurality of microneedles during shipping and storage, as well as fordisposal after its use.

In a preferred embodiment, as illustrated in FIG. 1A, the tab portion112 is substantially free of the adhesive layer, enabling a personhandling and applying the patch to do so without contacting the adhesivelayer 118A. In some embodiments, as illustrated in FIG. 1B, the adhesivelayer 118B may be disposed over substantially all of a side of thebacking layer 110, including the tab portion 112. A cover portion 120may be disposed over the adhesive layer 118 over the tab portion 112 sothat a person holding the patch by the tab portion does not contact muchor any of the adhesive layer.

In some embodiments, the adhesive layer 118 is a differential adhesive.As used herein, a “differential adhesive” may have a differentcoefficient of adhesion between various types of substrates. Forexample, a differential adhesive may have a coefficient of adhesionbetween the base substrate and the backing layer greater than thecoefficient of adhesion between the backing layer and the patient'sskin. Similarly, the coefficient of adhesion between the base substrateand the backing layer may be greater than the coefficient of adhesionbetween the backing layer and the tray or container in which it isstored. The coefficient of adhesion between the backing layer and thetray or container in which it is stored may be greater or less than thecoefficient of adhesion between the backing layer and the patient'sskin.

By having differential degrees of adhesion, the patch can be removedfrom the tray or container relatively easily, adhered to the skinfirmly, and removed from the skin when administration is complete, whilestill keeping the base substrate affixed to the backing layer throughoutits use. Such differential adhesion also may be obtained by using morethan one type of adhesive (e.g., a first adhesive between the basesubstrate and backing layer and a second adhesive beyond the basesubstrate and backing layer), modifying the amount, thickness, and/orpattern of adhesive that is applied, or using a coating/release liner orother features to modify the coefficient of adhesion.

In some embodiments, the backing layer may include a label disposed onthe back side of the backing layer opposite the adhesive layer. Thelabel may be printed directly onto the backing layer or attached to thebacking layer. Such a label may be used to provide various types ofinformation useful to the caregiver and/or patient. For example, thelabel may provide an API identity and dosage in the patch, productserial number or batch information, instructions for administration,expiration date, and the like. In some embodiments, the label may beincorporated directly into a handle layer that is distinct from thebacking layer.

Microneedle Patch Storage System

Turning back to FIG. 1C, the microneedle patch 100 may be housed on atray 122 having an upper surface region surrounding one or more recessedregions 124. The one or more recessed regions 124 may be dimensioned toreceive in a non-contacting manner the one or more microneedles 114 of acorresponding microneedle patch 100, with the adhesive layer of themicroneedle patch being releasably secured to the upper surface regionof the tray. Because contact between the tray and microneedle patch islimited substantially to the adhesive layer and/or backing, theintegrity of the one or more microneedles is advantageously retainedduring storage. In addition, the tray may also protect the one or moremicroneedles from moisture, gases, or other contaminants that coulddegrade the substance of interest, reduce the shelf life, or diminishthe effectiveness of the substance of interest.

The trays may take a variety of shapes and sizes, such as therectangular shape illustrated in FIGS. 3A-B, the planar shape with aformed cap illustrated in FIGS. 4A-B, or the partial ellipsoidal shapeillustrated in FIGS. 5A-B. The tray may further include one or moreadditional features with various functions or to impart a desiredaesthetic to the tray. For example, the tray may include one or moredepressions (FIGS. 3A-3B), holes, or cutouts (FIGS. 13A-B). Suchfeatures may facilitate removal of the microneedle patch from the tray.The recessed region for receiving the one or more microneedles also maybe positioned in the tray such that at least a portion of the tabextends over the perimeter of the tray (FIGS. 3B, 4B, 5B).

A variety of materials may be used to make the trays provided herein,non-limiting examples of which include polymers (e.g.,polytetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP),polyvinylidene fluoride (PVDF), polyvinyl fluoride (PVF), polyethylene,or polypropylene), metallized polymers, elastomers, non-woven and wovenmaterials, paper-based materials, foam, metal or foil, and the like. Insome embodiments, the tray may be formed of composite materials ormultilayer materials. For example, a multilayer material may include oneor more layers that impart the desired structural properties and one ormore layers that impart the desired barrier properties.

In one embodiment, the tray includes a coating on one or more surfacesof the tray. For example the tray may include coatings that providemoisture and gas barrier properties to the recessed region where the oneor more microneedles are contained, coatings that include desiccant, orcoatings that facilitate release of the microneedle patch from the tray(e.g., a release liner or the like). For example, the tray may be coatedwith a material (e.g., silicone, oils, wax, PTFE) that has a low surfaceenergy (e.g., ≤30 dynes/cm, preferably ≤20 dynes/cm) so that the patchcan be readily peeled off of the tray. The tray also may include certainsurface patterns or textures (e.g., bumps, ridges, holes, etc.) thatreduce the contact area between the adhesive layer and the tray tofurther aid removal of the patch from the tray. The tray also mayinclude one or more nesting features (e.g., matingly dimensioned raisedand recessed areas) that facilitate stacking of multiple trays.

A tray may be configured to house a single patch or a plurality ofpatches (e.g., 2, 3, 4, 5, 6, 7, 8, 10, 12, or 20 patches, or more orless). FIGS. 13A-B illustrates a tray having 10 microneedle patchesstored in two rows of five. In one embodiment, the tray includes aplurality of recesses, with each recess corresponding to one of themicroneedle patches. The trays also may include one or more lines ofweakness (e.g., perforations, score lines, and the like) so thatportions of the tray are separable from other portions of the tray. Insome embodiments, the patches may be stored on only one side of thetray, while in other embodiments, the patches may be stored on bothsides of the tray (e.g., with recessed regions on both sides of thetray). In still other embodiments, the tray may have a three-dimensionalgeometry, such as a cube, with recessed regions for housing the patcheson all sides (e.g., six sides for the cube). Thus, the trays may bedesigned such that a plurality of patches may be efficiently stored(e.g., the center-to-center spacing of the recessed regions may beapproximately equal to the center-to-center spacing of the patches) suchthat a majority of the tray surface is covered by patches.

These trays, together with the patch, may alone be sufficient to protectthe microneedle patch prior to use; however, additional features alsomay be used. For example, one or more trays may be disposed in aflexible container (e.g., pouch) and/or rigid container (e.g., box). Insome embodiments, a lid may be disposed on the tray to protect themicroneedle patch prior to use. Such lids may be the same or a differentmaterial from the tray, and may be sealed to the perimeter of the tray(i.e., using a heat seal, cold seal, or pressure sensitive adhesive). Inone embodiment, a desiccant may be provided in the recessed regions orin the flexible or rigid container housing the tray. A desiccant mayalternatively or in addition be part of the tray itself. For example, adesiccant material may be included (e.g., dispersed in or coated onto)the material forming the structure of the tray. For example, the traymay be formed of a desiccant polymer known in the art.

In addition to the protective function prior to use, the trays providedherein also improve ease of handling of the microneedle patches andrequire less material than other types of microneedle patch packaging,thereby reducing both cost of handling and materials. Moreover, thetrays also may be used for disposal of a used microneedle patch byapplying the patch to the tray such that the remaining one or moremicroneedle substructure, any residual substance of interest, orbiological waste is contained within the recessed region.

The trays may be formed using a variety of different methods,non-limiting examples of which include various molding methods (e.g.,thermoforming, injection molding, stamping, casting), 3-D printing,machined, laser sintered, and the like. In embodiments in which the trayhouses a plurality of microneedle patches, it may be desirable tomanufacture the microneedle patches in multi-patch cards or webs. Inthis way, the multiple patches are all attached to each other at onepoint during the manufacturing process, and may be configured such thatthe geometry of the microneedle patches during manufacture matches theconfiguration in which the microneedle patches are disposed on the tray.During the manufacturing or subsequently, a plurality of microneedlepatches may be applied substantially simultaneously to the tray. In someembodiments, one multi-patch card may be applied per tray.Alternatively, a plurality of multi-patch cards may be applied per tray.After application of the multi-patch card to the tray, the backing layerof the patches may be weakened (e.g., perforated, scored, or cut) sothat the patches are no longer contiguous or are easily separable by auser. In some embodiments, the microneedle patches may be formed by amolding process using a mold that also functions as the tray or as acomponent of the tray. In such instances, the microneedles would notrequire removal from the mold during the manufacturing process and couldinstead be removed from the mold prior to application by a user.

Feedback Indicators

In another aspect, various indicators are provided with the microneedlepatches. The indicators provide a mechanism for providing a user withfeedback to assist with the proper and effective use of the microneedlepatch. The feedback may be provided in a variety of forms orcombinations, including visual (e.g., change in color or other physicalappearance of the patch), tactile (e.g., a detectable sensation felt bythe person administering the patch or patient), audible (e.g., thepresence, absence, or change of sound), olfactory (e.g., a release of afragrance upon dissolution of the microneedles or upon wetting of thepatch), gustatory (e.g., a change of taste observed by licking the patchbacking layer until a specific taste is detected or observed inapplication of the patch to mucosal tissue (e.g., for treatment of adental condition or for a mucosal vaccination), such as sweet, salty,sour, or bitter). Alternatively, the feedback may be indirect and thenconverted into such a signal, or may be converted between differenttypes of signals (e.g., an electronic communication transmitted to anelectronic device, such as a computer, tablet, or smart phone).

The indicators generally may be characterized as having an initialconfiguration before providing the feedback signal, and a signalingconfiguration which differs from the initial configuration and whichprovides the feedback signal. In some embodiments, the signalingconfiguration is reversible, such that the indicator may return to itsinitial configuration after providing the feedback signal. In otherembodiments, the indicator assumes a third configuration (i.e.,different from the initial configuration and different from thesignaling configuration) after providing the feedback signal.

The feedback may be provided to a variety of “users”, including thepatient or a person or an organization other than the patient (e.g., ahealth care worker, caregiver, parent, guardian, patchmanufacturer/supplier, regulatory agency, insurance company, and thelike). In some instances, the feedback may be provided to a remotedevice that interacts with the microneedle patch (e.g., an electroniccontroller) by receiving feedback and providing output in response todirectly alter the operation of the microneedle patch or to provideinformation to a person who can use that output information, potentiallyto alter microneedle patch operation.

Application Force/Pressure

In a preferred embodiment, the feedback indicator is or includes amechanical force indicator that can be used to indicate to the user theamount of force and/or pressure applied to the patch during itsadministration. For example, in one embodiment, the indicator isconfigured to provide a signal when a force applied to the patch by auser (in the course of applying the patch to a patient's skin to insertthe one or more microneedles into the patient's skin) meets or exceeds apredetermined threshold. The predetermined threshold is the minimumforce or some amount greater than the minimum force that is required fora particular microneedle patch to be effectively applied to a patient'sskin. That is, it is the force needed to cause the microneedles to beproperly, e.g., fully, inserted into a patient's skin.

The mechanical force indicator can signal to the user in a variety ofdifferent ways that the predetermined threshold has been met orexceeded. In one embodiment, the mechanical force indicator may changefrom its initial configuration to its signaling configuration uponreceiving a force which meets or exceeds the predetermined threshold.

In advantageous embodiments, the microneedle patch is configured suchthat the microneedles will properly penetrate the patient's skin beforethe mechanical force indicator changes to its signaling configuration.That is, the patch can be properly applied independently of operation ofthe mechanical feedback indicator. In contrast, certain conventionalmicroneedle patches require some type of patch deformation to occurbefore the microneedles are inserted into the skin.

In one embodiment, the mechanical force indicator operates based onmaterial deformation or fracture of a component of the indicator. Forexample, a structural feature may deform or fail once the predeterminedthreshold force is met or exceeded. Such a deformation or failure may becomplete or partial. In different embodiments, the deformation may beplastic or elastic; it may be reversible or irreversible. Non-limitingexamples of materials that undergo such deformation include metals,polymers, viscoelastic materials, bi-phasic materials, and the like. Themechanical force indicator may include one or more springs.

One embodiment of a mechanical force indicator that undergoes materialdeformation or failure is shown in FIG. 7 . Here, the microneedle patch700 includes a mechanical force indicator 710 attached to an uppersurface of the patch (opposite side from the microneedles). Theindicator 710 includes a snap dome 720, which may be a bi-phasicmaterial. The snap dome is designed to collapse (deform) uponapplication of a sufficient force, which meets or exceeds thepredetermined threshold. Upon removal of the force, the bi-phasicmaterial may remain partially or completely deformed or maysubstantially return to its original curved shape. Advantageously, thecollapse may emit a snapping sound, is clearly visible, and/or can befelt by the user's finger used to apply the patch. In this way, the snapdome provides tactile, visual, and audible signals to the user that thethreshold force is met or exceeded and that the patch has been properlyapplied to the patient's skin.

As used herein, “bi-phasic material” refers to a material that does notdeform continuously under pressure, but rather adopts one shape in itsinitial configuration and another shape in its signaling configuration.An exemplary type of bi-phasic material is a “snap dome” or “button”,which consists of one or more parts that deform under pressure. Forexample, snap domes having a single non-planar part may remain wholeafter deformation or break and separate into two or more parts afterdeformation. Alternatively, snap domes having two or more parts maybecome joined together to form a single part after enough pressure hasbeen applied (e.g., a snap having a male part and a female part). Aparticular snap dome may be selected such that the actuation forcerequired to deform the snap dome is equal to or higher than thepredetermined threshold force required for effective microneedleinsertion.

Two exemplary mechanical force indicators comprising snap domes areshown in FIG. 2A and FIGS. 6A-6C. In FIG. 2A, a microneedle patch 200includes a microneedle array 214 on a base substrate 216. Themicroneedle array 214 is affixed to a backing layer 210 including a tabportion 212 by an adhesive layer 218. An adhesive cover 220 is disposedon the portion of the adhesive layer 218 over the tab portion 212. Amechanical force indicator 222 is disposed between the adhesive layer218 and backing portion 210. The mechanical force indicator 222 may be anon-planar disc or dome that deforms upon application of the thresholdforce. In FIGS. 6A-6B, the indicator 300 includes a non-planar disc 312disposed in its own housing formed by a disc-shaped tray 314 and abacking material 310. The disk may be constructed of a suitable metal orpolymer. An adhesive layer 316 may be used to affix the indicator 300onto either the opposing back side of the backing layer (FIG. 6C) or thebase substrate (not shown).

In another embodiment, the mechanical force indicator includes aviscoelastic material. Such materials may be selected based on thedesired stiffness or Young's modulus, so that the force required todeform the materials (i.e., fully or partially compress in thisinstance) is equal to or higher than the predetermined threshold forcerequired to verify proper microneedle insertion. Non-limiting examplesof viscoelastic materials that may be used include foams (e.g.,polyurethane, silicone, polyethylene, nitrile), elastomers (e.g.,polyurethane, silicone, nitrile, butyl, polyacrylic, fluoroelastomers),and other viscoelastic materials known in the art.

In still another embodiment, the mechanical force indicator may includea spring. For example, a spring may be selected with a desiredcombination of spring rate and deflection length. The more forcerequired, the higher the spring constant and/or greater deflectionlength of the spring. Thus, the spring and its rate may be selected suchthat the force required to fully or partially compress the spring isequal to or higher than the predetermined threshold force. The springmay be in the form of a compression spring consisting of a coiled wire(most commonly with a circular cross-section, but other wirecross-sections may be desirable including square, rectangular, oval,etc.) with a constant diameter or cross-sectional dimension, or may be aconical spring or tapered spring (e.g., with a tapering diameter).Conical springs may be compressed flat and have a relatively uniformrate constant throughout its entire deflection length (unlike standardcompression spring rate constants that increase rapidly toward themaximum deflection length). With any of the foregoing springs, it may bedesirable to mechanically maintain the spring in asubstantially-compressed state to provide a thinner initial springmechanism in order to provide a lower profile patch (i.e., flatter);however, other types of springs that are flatter and provide the desiredfeedback through a very small total deflection may be desirable.Non-limiting examples of flat springs include finger springs, disc orwasher springs, wave springs, and the like. Springs are commonly madefrom metals or alloys (e.g., spring and stainless steels), but can alsobe made from plastics, elastomers (e.g., urethane springs, which aregenerally tubular in shape), and other materials. A spring-like effectalso can be obtained using a gas in a sealed compartment (i.e., a gasspring), the deflection of which may be reversible or irreversible. Forexample, a plastic blister (or balloon) filled with air compresses whenpressed on. Once the desired predetermined threshold force is applied,the blister will pop due to material failure under pressure, therebyproviding the user with tactile, audible, and/or visual signals.

The foregoing mechanical force indicators may be reversible orirreversible (e.g., as determined by whether it can return to itsinitial configuration after changing to its signaling configuration).For example, in the case of a spring or viscoelastic material, thespring or viscoelastic material may regain its initial shape. However,such indicators also can be configured to undergo irreversibledeflection or displacement by integrating them with other components,such as snap-in-place mechanism where the spring becomes stuck withinanother part or where two separate parts latch together (e.g.,finger-ledge mechanism, snap mechanism, hook and loop, pressuresensitive tape, press-fit held in place by interference friction,magnetic) when the spring and other material are fully engaged. In thecase of material failure (e.g., by fracture), the change will beirreversible. The indicator may also be partially reversible, in whichthe indicator partially, but not fully, returns to its initialconfiguration.

Still other types of mechanical force indicators may be used to indicatewhen a predetermined threshold force is applied to the microneedlepatch. For example, the mechanical force indicator may cause adetectable change to one or more materials that are an integral part ofor attached to the backing layer of the microneedle patch. Non-limitingexamples of such detectable changes include changes in color or colorintensity, wetness appearance, texture, and/or temperature. One suchmaterial change may be provided by a surface pressure-indicating filmthat reveals pressure distribution and magnitude by virtue of a colorchange or color intensity change. Another exemplary material is one thatmay deform when pressed on by the finger or thumb during itsadministration to a patient's biological tissue and retains, eitherpermanently or temporarily, the finger/thumb imprint (e.g., such as theabove-described viscoelastic materials). Yet another exemplary materialis one that which, when compressed, makes a sound (e.g., as a result ofair being forced out of the material or as a result of friction betweenobjects such as beads or pellets contained within the material).

FIG. 8 illustrates one embodiment of a feedback indicator based onvisual color cues. In this embodiment, the feedback indicator includes adye or ink 820 that is contained within a reservoir (e.g., such as ablister or capsule that breaks upon application of a given force andreleases the dye) in the backing layer 810 (or another layer) of themicroneedle patch 800. Upon meeting or exceeding the threshold force,the dye 820 is released from the reservoir so that a change of color isobservable in at least part of the patch. In one embodiment, illustratedin FIG. 8 , the dye 810 is released into the backing layer 810 oranother layer of the microneedle patch, providing a visual signal that asufficient force was applied. In another embodiment, the dye istransferred from the reservoir to the finger or thumb of the personapplying the microneedle patch to the patient. In still anotherembodiment, the dye diffuses from one portion of the patch to anotherportion of the patch. The diffusion of the dye within the patch also mayact as an indicator of the wear time of the patch.

FIG. 10 illustrates another embodiment of a feedback indicator based onvisual color cues. In this embodiment, diffusion of a dye from one areaof the patch to another area of the patch occurs after the predeterminedthreshold force is applied to the microneedle patch. The microneedlepatch 1000 includes a dye 1020 located in a portion of the patch beneathan opaque barrier 1010 attached to an upper surface of the patch(opposite side from the microneedles). Upon application of thepredetermined threshold force, the dye 1020 begins to move to anotherportion of the patch. After a period of time, the dye 1020 reachesanother portion of the patch that is not covered by an opaque barrier1010 so that it can be seen by a user, thereby providing an indicationthat the patch has been applied to the patient's biological tissue, suchas the skin, for a sufficient amount of time to ensure release of thesubstance of interest (e.g., a therapeutically effective amount of theAPI).

FIGS. 12A-12C illustrates yet another embodiment of a feedback indicatorusing dye movement. In this embodiment, a dye 1230 is provided in themicroneedle patch 1200 in a recessed portion 1220 of indicator structure1210 and then contacts the finger or thumb of a user applying pressureto the patch only when the force applied by the user reaches or exceedsthe predetermined threshold force. That is, the application force mustmeet or exceed the predetermined threshold force in order tosufficiently compress the indicator structure 1210 defining the recessedportion 1220 containing the dye 1230, so as to permit the finger orthumb to contact the dye 1230.

In another embodiment, a porous material, such as a sponge, contains adye that, upon application of the predetermined threshold force,releases the dye. In still another embodiment, a material is coated witha dye that is transferred to the person administering the patch or apatient upon application of the predetermined threshold force. FIG. 11illustrates an embodiment in which the microneedle patch 1100 has a basesubstrate 1120 that is coated on the microneedle side with a dye 1130which is transferred to the patient's skin when a sufficient force isapplied to the patch to cause the microneedles 1110 to be effectivelyinserted into the skin, such that the dye on the base substrate contactsand is transferred to the patient's skin. This dye transfer indicatesproper/complete microneedle insertion.

Still other embodiments of mechanical force indicators may include apiezoelectric sensor or other electrical components. For example, apiezoelectric sensor may generate a voltage or current upon applicationof a predetermined threshold force. A transducer may be an integral partof the microneedle patch or may be attached to the backing layer oranother component of the microneedle patch. An exemplary piezoelectrictransducer may include a ceramic (e.g., barium titanate) sandwichedbetween two conductive plates or surfaces (e.g., copper). The transducercan be connected to a digital voltmeter or amp-meter to provide avoltage/current readout to signal whether a predetermined thresholdforce has been applied. The volt-/amp-meter may be an integral part ofthe microneedle patch or built into an applicator-like device that canbe used to apply the microneedle patch. It also may be separate from themicroneedle patch and connected to the piezoelectric transducer duringadministration of the microneedle patch.

In another embodiment, a microneedle patch may be configured such thatan electrical circuit is completed upon application of the predeterminedthreshold. Two parallel, bendable conductive surfaces may be separatedby an insulator, foam-like, or spring-like material, for example, shapedin a doughnut fashion. Upon application of the predetermined thresholdforce, the person applying the patch causes the upper conductive surfaceto bend and travel towards the lower conductive surface (as theinsulator material is compressed between both conductive surfaces) untilboth conductive surfaces make contact and complete an electrical circuitthat creates a signal (e.g., a light or a sound) that sufficientpressure was applied.

In another embodiment, an electrical circuit can be completed using theconductivity of liquid. The conductive liquid could be held within acapsule or blister incorporated into the patch that bursts uponapplication of the predetermined threshold force, releasing theconductive liquid to make the electrical connection between twoelectrodes. Alternatively, the conductive liquid could be from the skinor other tissue (e.g., interstitial fluid) that diffuses into the patch.The electrodes can be in the form of parallel plate electrodes that forma low-volume sensor, co-planar, or other suitable geometries. In eithercase, a sufficient volume of the conductive liquid is required to bridgeboth electrodes to complete the circuit and create a signal (e.g., alight or a sound) that sufficient pressure was applied.

In still other embodiments, a mechanical force indicator may beconfigured to create a particular tactile feedback to a user uponapplication of the predetermined threshold force. For example, uponapplying the predetermined threshold force, a coldness/warmth or wetnessmay be produced from a material or object that is an integral part of orattached to the microneedle patch. In one embodiment, a material coatedon the microneedle side of the base substrate triggers a sensation(e.g., heat, cold, etc.) when the microneedles fully puncture thepatient's skin and the base substrate comes into contact with thepatient's skin. Non-limiting examples of other types of tactile feedbackinclude vibration, pain, hardness/softness, slickness/slipperiness,smoothness/roughness, softness/hardness, sharpness, pattern recognition,proprioception, kinesthesia, texture recognition, topagnosis, two-pointdiscrimination, barognosis, and/or graphesthesia.

Microneedle Insertion, Dissolution, and Patch Wear Time

In another aspect, the feedback indicator provides information to theuser (and/or patient) that (i) the microneedles have penetrated the skinand/or that the substance of interest has been released into the targettissue. Such indicators may be especially useful to provide a userconfidence that the substance of interest was effectively delivered,particularly where delivery of the substance of interest is dependentupon insertion and dissolution of the microneedles or coating. Theindicator may measure full or partial microneedle dissolution, dependingon whether full or partial dissolution is needed for delivery of aneffective amount of the substance of interest. For example, by measuringfull dissolution, the indicator can signal to the user that themicroneedle patch can be removed from the patient's skin.

It also may be useful in some circumstances for the indicator to signalpartial dissolution if the partial dissolution would be sufficient toprovide an effective amount of the substance of interest or to otherwisesignal that user interaction with the microneedle patch is necessary ordesirable. Another situation where detection of partial dissolution maybe desirable is if multiple substances of interest are disposed in orcoated onto the microneedles, with sequential release of the multiplesubstances of interest being provided by progressive dissolution. Insuch situations, it may be beneficial for a medical professional to benotified when each of the multiple substances of interest are releasedby an indicator that signals each of the various stages of dissolution.

In some embodiments, the indicator may signal or detect dissolution ofindividual microneedles or particular groups of microneedles (e.g.,specific rows) within patch. Such an indicator could be useful if groupsof microneedles are configured to be delivered at different times (e.g.,to achieve controlled release of one or more substances of interest orif various microneedles are loaded with different substances of interestthat it is desirable to release at different time points). In someembodiments, the indicator also may signal when the microneedlesseparate from the base substrate. Such embodiments would be appropriatefor microneedles that are configured to separate from the base substrateupon insertion into the patient's skin or shortly thereafter, and wouldbe advantageous where it is neither practical nor desirable to leave thepatch on the patient's skin during dissolution of the microneedles, asmay be the case of patients that are intentionally or unintentionallynon-compliant.

One type of indicator for measuring insertion and/or dissolution of themicroneedles is by the wetting of the backing layer (or other suitablelayer) and/or diffusion of moisture in the backing layer. As usedherein, “wetting” means an increase in liquid content. Typically, thewetting of the patch occurs after insertion of the microneedles into atissue that contains fluid, with moisture from the skin, tissue, orinterstitial fluid entering into the microneedles, backing layer, and/orother parts of the patch while the patch is inserted into and adhered tothe tissue. The wetting may be detectable without an additionalindicator or may trigger one or more changes in color, texture, shape,or the like. Often, the release of a substance of interest from themicroneedles into the tissue is mediated at least in part by the entryof water into the microneedles. Such an indicator may be particularlybeneficial for detecting whether all of the microneedles were partiallyor fully inserted, the substance of interest contained in themicroneedles was successfully delivered, or the fluid/analyte wassuccessfully collected (e.g., in the case of a diagnostics application,etc.), and/or as a measure of patch wear time (e.g., the patch becomeswetted after it has been applied to the skin/tissue for a timesufficient for the microneedles to dissolve or separate from the base).

In some embodiments, the wetting of the patch by interstitial fluidfollowing insertion can be detected by a change in the refractiveproperties/index of the microneedles, rendering the microneedleinsertion sites (holes) visible through a transparent microneedle patch(i.e., backing, body, adhesive, and base). The refractive change mayinclude a lack of color (i.e., achromatic) to presence of a color (orvice versa), a weaker to a stronger color intensity (or vice versa), ora change of color (e.g., red to green). Such an indicator could be usedto signal penetration of the microneedles, dissolution of themicroneedles, and patch wear time.

In an embodiment, the patch wear time required for effectiveadministration of the substance of interest may be measured by adiffusive indicator whose length is equal to or longer than an expectedtime of delivery. The diffusive indicator may be triggered by moisturefrom the skin, tissue, and/or interstitial fluid, such that once thepatch is applied to tissue, or shortly thereafter, the diffusive processstarts. The diffusive indicator also may be triggered mechanically, forexample, by application of pressure on the patch during its applicationto release a fluid in the patch, or by some other means once the patchis applied (see FIG. 10 ). An exemplary embodiment of a microneedlepatch 900 including a diffusive indicator in an upper surface 910 of thepatch 900 is illustrated in FIG. 9 . In FIG. 9 , fluid 920 from the skinbegins to enter the patch 900 upon application of the patch 900 to theskin. Over time, fluid 920 moves through the patch 900 and the uppersurface 910 of the patch where it comes into contact with a colorindicator 930, providing a signal in the form of a color change inducedby the fluid 920 contacting a color indicator 930.

Another diffusive indicator that may be used to signal microneedlepenetration, dissolution, and/or patch wear time may involve a chemicalreaction. For example, once the diffusion process occurs, a chemicalreaction occurs to provide a detectable signal (e.g., a color change).Alternatively, the chemical reaction may be diffusion controlled orotherwise have a delayed onset (e.g., by fluid diffusing to contact achemical reactant). Such chemical reactions also may be triggered, atleast in part, by a mechanical trigger that releases the chemicalreactant following rupture of a reservoir containing the chemicalreactant, similar to the above-described mechanisms involving a dye.

In some embodiments, the chemical reaction may have a reaction time thatis equal to (or longer than) the desired patch wear time. The reactionmay be triggered at the time the patch is removed from its packaging(e.g., oxidation from exposure to air) or at the time it is applied tothe skin (e.g., wetting of the patch). Another embodiment may include achemical reaction that is triggered by removal of a component of thepatch before or after application of the patch to the patient's skin(e.g., following removal of a release liner to expose a chemicalreactant to air or light).

Another indicator that may be used to detect penetration and/ordissolution of the microneedles and/or patch wear time may includerelease of a dye onto a tissue (e.g., skin) or into surrounding tissue.For example, the dye may be encapsulated inside the microneedles orcoating such that the dye is released upon the dissolution of themicroneedles or coating. In some embodiments, the dye may change colorwhen released from the microneedles into the tissue (e.g., may have nocolor when in the microneedles and change color when released or viceversa). In some embodiments, the dye may not change color, but may notbe visible in the microneedles and become visible once released from themicroneedles. Because of the microneedle's size, a dye or other colorantloaded disposed in the microneedles and/or a coating may not be veryvisible to the naked eye; however, the release and spread of the dyeinto the tissue upon dissolution of the microneedles becomes much morevisible and obvious to the naked eye.

Similarly, in embodiments, the dissolution of the microneedles orcoating and release of the substance of interest also can be measuredindirectly, for example, by detecting or observing an effect of theadministered substance of interest or by detecting or observing therelease of a surrogate for the substance of interest. For example, ifthe actual release of the substance of interest cannot be detected ormeasured, the indicator may be designed to detect or measure the releaseof a surrogate substance (e.g., included in the microneedle, the releaseof which correlates with the release of the substance of interest). Foranother example, the dissolution of the microneedles or drug coating maybe measured by a specific local or systemic effect/sensation/feeling ora change that can be detected by the patient and/or a personadministering the patch (e.g., skin color change in the case of asubstance of interest with vasoconstrictive properties).

In another embodiment, an indicator may be used to detect patch weartime may include a dye that evaporates or fades during administration ofthe patch. For example, a dye may be used to print text or an image onthe backing layer of the patch. A protective layer disposed over thetext or image may be covered with a protective layer to prevent itsevaporation or fading prior to administration. After application of thepatch to a patient's skin, the protective layer may be removed (e.g.,peeled off) to expose the dye. The dye or ink may be configured toevaporate or fade (e.g., due to oxidation or exposure to light) over acertain amount of time. Thus, the disappearance of the dye signals thatthe patch can be removed from the skin.

Integrity and Storage of Microneedles

Indicators also can be provided to detect the integrity of themicroneedles following storage and shipping, including the measuring thetemperature, humidity, or vibrations/force that the patch has beenexposed during storage and shipping. Such indicators can be integratedinto the patch itself and/or the packaging. Such indicators may beuseful to determine whether the patch was stored at appropriateconditions before being used, as the functionality and stability of thesubstance of interest and the integrity of the microneedles may beadversely affected if the patch is exposed to deleterious conditions(e.g., extreme temperatures, humidity, or vibrations/force).

In embodiments, an indicator for measuring the storage temperature mayinclude a vaccine vial monitor (VVM) or similar technology that willprovide a signal (e.g., change of color) if exposed to excessivetemperature over time. The VVM can be integrated within the patchpackaging or the patch itself (e.g., part of the backing layer). In someembodiments, the indicator may be in the form of a thermochromicmaterial, and is a component of or applied as a sticker to the backinglayer or patch packaging. The VVM or similar technology may be used todetect exposure to a threshold temperature at or above which damage tothe substance of interest will occur or integrated time-temperatureexposure where both the exposure time and the temperature(s) to whichthe patch is exposed are taken into consideration. Integratedtime-temperature exposure may be assessed via a material phase change, achemical reaction, an electronic device and other methods known in theart.

In embodiments, an indicator for measuring the level of humidity a patchis exposed to during storage and transport may be assessed usinghumidity indicating dyes. Such dyes change color due to exposure tocertain humidity levels, and may be incorporated within the patch orpatch packaging. For example, the humidity indicator may be in the formof a card that shows a number of humidity ranges or just a single spotthat changes color if the humidity rises above a certain threshold. Suchcards may be based on cobalt (II) chloride base, copper (II) chloridebase, or similar chemistry. Alternatively, the humidity indicator may beincorporated within desiccant included in the packaging that is visibleto the user or healthcare provider prior to application of the patch.Humidity indicators also may be measured using an electronic devices(e.g., a humidity meter) that are an integral part of the patch orpackaging; or by a water-sensitive degradation, reaction, or phasechange; by hygroscopic and/or deliquescent material (e.g., material thatwill readily absorb moisture and undergo some reaction or some otherphysical change). Non-limiting examples of deliquescent materialsinclude salts (e.g., calcium chloride, magnesium chloride, zincchloride, potassium carbonate, potassium phosphate, carnallite, ferricammonium citrate, potassium hydroxide, and sodium hydroxide), and somesugars that undergo a phase change from solid to liquid upon absorptionof moisture from air.

In embodiments, indicators for detecting excessive vibration/force mayinclude a component of the patch or packaging (e.g., a protective cap)configured to collapse and deform or break if it is subjected to a forcethat would otherwise compromise the structural integrity of microneedlesor any other component of the patch. In another embodiment, anaccelerometer or shock and drop indicator may be incorporated into thepatch or its packaging to detect vibration or shock the microneedlepatch may be subjected to during storage and/or transport. A shock anddrop indicator will activate when an impact level exceeds apredetermined level (level that will compromise the microneedle patch),and may be in the form of a device with a specific sensitivity or in theform of go/no-go device that indicates whether the patch packaging hasbeen dropped during storage or transport.

It will be appreciated from the foregoing that certain indicatorsadvantageously may be capable of providing multiple forms of feedback.For example, a snap dome can be used to provide feedback about thepressure applied to patch, wear time and/or dissolution (e.g., bydelayed reversibility of deformation), and/or patch exhaustion/use(e.g., by irreversible deformation). A mechanical force indicatorincluding a reservoir of dye can be used to provide feedback about thepressure applied to the patch during use, wear time and/or dissolution(e.g., by diffusion of the dye), patch exhaustion/use (e.g., by changeof color), and/or exposure to extreme vibrations/force during shippingand handling (e.g., if the reservoir is ruptured prior to use such thatthe dye is released into the patch or within the patch packaging).

The above-described indicators also may be used to provide other typesof signals and feedback. For example, one or more indicators thatprovide feedback that the patch has been removed from its packaging oradministered may trigger an authorization of payment for treatment. Inanother embodiment, one or more indicators that provide feedback thatthe patch has been successfully administered may be used to verifycompliance with a requirement that the patient undergo treatment (e.g.,a school, employer, government, or military requirement for certainvaccinations/treatments). In an embodiment, one or more indicators thatprovide feedback of successful patch administration may be used toprotect healthcare providers, manufactures, and distributors fromliability. In an embodiment, one or more indicators that providefeedback regarding various aspects of the patch administration may beused by the manufacturer or healthcare provider to modify the design oradministration of the patch or to aid with logistics relating to supplyof the patch (e.g., when and how many patches to manufacture anddistribute).

Substance of Interest/Active Pharmaceutical Ingredient

A wide range of substances may be formulated for delivery to biologicaltissues with the present microneedle patches and methods. As usedherein, the term “substance of interest” includes active pharmaceuticalingredients, allergens, vitamins, cosmetic agents, cosmeceuticals,markers (e.g., colored dyes or radiological dyes or markers), and othermaterials that are desirable to introduce into a biological tissue, inparticular into a tissue of a human or other mammal, including but notlimited to the skin of human or other mammal. In an alternativeembodiment, the biological tissue is a plant tissue.

In one embodiment, the substance of interest is a prophylactic,therapeutic, or diagnostic agent useful in medical or veterinaryapplications. In one embodiment, the substance of interest is aprophylactic or therapeutic substance, which may be referred to hereinas an API. In certain embodiments, the API is selected from suitableproteins, peptides and fragments thereof, which can be naturallyoccurring, synthesized or recombinantly produced. Representativeexamples of types of API for delivery include antibiotics, antiviralagents, analgesics, anesthetics, antihistamines, anti-inflammatoryagents, anti-coagulants, allergens, vitamins, antineoplastic agents,antigens, and toxins. In one embodiment, the substance of interestcomprises a vaccine.

A microneedle patch may include a single substance of interest or it mayinclude two or more substances of interest. In the latter case, thedifferent substances may be provided together within one of themicroneedles, or some microneedles in an array of microneedles containone substance of interest while other microneedles in the array containanother substance of interest.

The API desirably is provided in a stable formulation or composition(i.e., one in which the biologically active material therein essentiallyretains its physical stability and/or chemical stability and/orbiological activity upon storage). Stability can be measured at aselected temperature for a selected period. Trend analysis can be usedto estimate an expected shelf life before a material has actually beenin storage for that time period.

In embodiments, the substance of interest is provided as a solid that is“dry” or has been “dried” to form (e.g., in combination with a matrixmaterial) at least a portion of the one or more microneedles or aportion of a coating on a microneedle sub-structure that becomessolubilized in vivo following insertion of the microneedle into thepatient's biological tissue. As used herein, the term “dry” or “dried”refers to a composition from which a substantial portion of any waterhas been removed to produce a solid phase of the composition. The termdoes not require the complete absence of moisture (i.e., the API mayhave a moisture content from about 0.1% by weight and about 25% byweight).

The substance of interest may be included in a formulation with one ormore excipients and other additives that are used in pharmaceuticalformulations. Non-limiting examples of such excipients includestabilizers, buffers, bulking agents or fillers, adjuvants, surfactants,disintegrants, antioxidants, solubilizers, lyo-protectants,antimicrobials, antiadherents, colors, lubricants, viscosity enhancer,glidants, preservatives, materials for prolonging or controllingdelivery (e.g., biodegradable polymers, gels, depot forming materials,and others). The excipients may be FDA approved excipients (such asthose listed in the FDA's Inactive Ingredient Search for Approved DrugProducts) or may be novel, and may be effective to perform more than onefunction (e.g., a sugar may be used as a stabilizer and a bulking agent,a buffer may be used to both buffer pH and protect the substance ofinterest from oxidation). The one or more selected excipients desirablyimprove the stability of the substance of interest during drying andstorage of the microneedle patches.

Methods of Use

The microneedle patches provided herein may be self-administered oradministered by another individual (e.g., a parent, guardian, minimallytrained healthcare worker, expertly trained healthcare worker, and/orothers). Unlike prior art microneedle systems, the microneedle patchesprovided herein may be directly handled and administered by the personapplying the patch without requiring use of an applicator to apply therequired force/pressure, thereby allowing for a very simple, low-profile(i.e., thin and patch-like) microneedle patch.

Thus, embodiments provided herein further include a simple and effectivemethod of administering a substance of interest with a microneedlepatch, illustrated in part in FIGS. 13A-13D. The method may includeidentifying an application site and, preferably, sanitizing the areaprior to application of the microneedle patch (e.g., using an alcoholwipe). If needed, the application site may be allowed to dry beforeapplication of the microneedle patch. The patch may be removed from thetray in which it is releasably secured by grasping the tab portion ofthe patch between the thumb and finger and peeling the patch from tray.The patch then is applied to the patient's skin/tissue and manuallypressed into the patient's skin/tissue (e.g., using the thumb or finger)by applying a sufficient pressure to insert the one or more microneedlesinto the patient's skin/tissue. After administration is complete, thepatch may be removed from the patient's skin/tissue by manually graspingthe tab portion (e.g., between the thumb and finger), peeling the patchoff the patient's skin/tissue, and discarding the patch.

In some embodiments, a user may use one or more indicators prior to,during, and/or after administration of the microneedle patch. Suchindicators may be elements incorporated into the microneedle patch thatprovide a detectable signal or may result from the user performing oneor more actions, such as evaluating the microneedle patch or patient'sskin/tissue following administration. Although such indicators may bepassive (e.g., providing the signal without user engagement, such as bythe diffusive mechanisms described above), such indicators also may beactive (e.g., requiring user engagement), or may be a combination ofpassive and active. For example, assessment of indicators at the patchlevel may be characterized as an “overall assessment”, whereasassessments made to the patch and/or skin/tissue by the user may becharacterized as a “regional assessment” (e.g., detection of a signalgenerated by the microneedle patch would be a passive, overallassessment, whereas inspection of microneedles following administrationof the patch would be an active, regional assessment).

Various indicators may be assessed by a user during application of thepatch to signal whether the patch has been properly applied and/or maybe removed. For example, in some embodiments an indicator provides asignal that a predetermined threshold force has been reached or that themicroneedles have penetrated/punctured the patient's skin, indicatingthat the user may discontinue applying pressure to the patch.Optionally, the signal may provide an indication that the user shouldcontinue applying the pressure for an additional specified time (e.g.,several seconds) prior to releasing the pressure. In some embodiments,another indicator provides a signal that administration is complete,indicating that the user may remove the patch from the patient'sskin/tissue. For example, the indicator may provide a signal thatspecified time period has passed or that the microneedles or coatinghave dissolved.

Indicators that provide a user with a signal that a sufficient period oftime has passed after applying the patch to the patient's skin/tissuecan provide a user with confidence that the substance of interest hasbeen successfully administered prior to removing the patch from thepatient's skin/tissue. This is especially useful in situations wheremonitoring (e.g., measuring) the patch wear time is not possible,practical, or desirable by the user and/or patient. For example, ahealthcare provider responsible for applying patches to multipleindividuals at different times would be able to apply the patch tomultiple individuals while checking at various time intervals whetherthe indicator signals that the patch wear time has lapsed and/or thesubstance of interest has dissolved. In this way, the healthcareprovider can provide care to multiple individuals during a given timeperiod without having to provide individualized attention to eachpatient during the entire administration period. Such an indicator alsowould provide a signal to the patient that the patch could be removed bythe healthcare provider or by the patient him/herself (or guardian)after leaving the doctor's office/clinic, or after administrationoutside the clinic (e.g., at home).

In addition to the above-described embodiments of indicators that may beeffective to determine whether a sufficient period of time has passedfor successful administration of the substance of interest, anotherindicator may include a clock, stopwatch, or other timing device (e.g.,optionally with an alarm to signal when a predetermined time period haspassed) integrally formed with the patch. In another embodiment, thepatch may include a backing layer onto which a user may write the timeat which the patch was applied or the time at which the patch may beremoved directly on the patch (or on any associated papers orpackaging).

Other types of feedback also may be used to determine whether asufficient period of time has elapsed and/or whether the microneedleshave successfully penetrated the skin/tissue or dissolved. For example,passage of a predetermined time period may be detected by an increase inthe temperature of the microneedle patch (e.g., as determined viatactile feedback or via a thermometer or other temperature-sensingmechanism that may be integral with the patch) for those instances inwhich a chilled microneedle patch that is refrigerated during storageincrease temperature following application onto a patient's skin/tissue.

Another type of feedback that a user may consider in evaluating whethera sufficient period of time has passed and administration of themicroneedle patch is complete includes the ability of the user to movethe patch on the skin/tissue surface. The microneedles inserted into theskin/tissue act as anchors for the microneedle patch. Once themicroneedles are dissolved, the patch is less anchored to theskin/tissue surface and can be more readily moved. Thus, an ability tomove the patch on the skin/tissue surface can be used to providefeedback that the microneedles have dissolved and the patch may beremoved from the patient's skin/tissue.

The quality or success of the microneedle administration also may beevaluated via other types of feedback after removal of the microneedlepatch, for example, by inspection of the patch or patient's skin/tissue.In an embodiment, feedback may be provided by evaluating the depth ofmicroneedle penetration by the presence or absence of blood on thesurface of the skin/tissue or in the holes formed by the microneedles(e.g., shallow insertion typically results in no or less blood beingpresent, while deeper insertion is more likely to puncture thecapillaries in the dermis to produce more blood). In another embodiment,feedback may be provided by a dye contained in the patch that isconfigured to stain the viable epidermis and/or upper dermis (or othertissue) at the puncture sites, such that a pattern of dye remainsfollowing washing away the excess dye. In still another embodiment,feedback of successful penetration may be provided by evaluating a filmapplied onto the application site where the patch is to be applied.Following application and removal of the patch, the film can beinspected for any signs of puncture either while on the skin or afterpeeling it off the skin/tissue. In some embodiments, the film may beconfigured such that a threshold force must be applied to pierce thefilm, the threshold force being sufficient for the microneedles to alsopierce the skin/tissue.

Feedback of microneedle penetration also may be gauged by measuring theelectrical resistance of skin, as a drop in resistance or a specificchange in resistance indicates puncture of the stratum corneum and maybe detected via either an electrode included in the patch or by using aseparate device to probe the application site after patch removal.

In still another embodiment, feedback may be provided by examining themicroneedle patch following administration. For example, the amount ofthe microneedles that dissolved (e.g., complete or partial dissolution)is a direct indication of the insertion depth. Therefore, if a portionof a microneedle did not dissolve, it is likely that this portion wasnot inserted into skin or did not remain inserted long enough todissolve sufficiently. Conversely, if the entire microneedle or asubstantial majority of the microneedle is gone after use, it is likelyan indication that the microneedle was completely or substantiallydissolved and the substance of interest was successfully administered.Similarly, if the microneedles included a dye and the patch lacked thatdye after administration, the absence of that dye would be an indicationthat the microneedle was completely dissolved and the substance ofinterest was successfully administered. Alternatively, different colorsassociated with different parts of the microneedle (i.e., for partialdissolution) may be used to identify whether the desired portion of themicroneedle was successfully administered.

Using the above-described indicators and feedback, a user will be ableto determine whether a patch has been successfully administered and willbe able to make an appropriate decision if it is determined that themicroneedle patch was not properly administered. For example, a user maybe able to increase the pressure applied to the patch so that themicroneedles penetrate the skin/tissue or may determine that anotherpatch can or should be administered.

The above-described indicators and feedback also may function to provideevidence that the microneedle patch has already been used, and may behelpful in situations in which the patch is not properly discarded afteruse (i.e., thereby avoiding attempts to reuse the patch, which wouldresult in an ineffective treatment, or potential exposure to abio-hazardous material that has been contaminated by the previouspatient's bodily fluids). Evidence of use of microneedle patches isparticularly helpful because the microneedles are such small structuresthat are barely visible with the naked eye.

Additional elements also may be included in the patch or additionalsteps may be taken during administration to provide such feedback. Forexample, a dye or other material may be applied to skin/tissue prior toapplication of the patch and at least a portion of the dye or othermaterial may transfer to the patch during its administration, therebyindicating that the patch has been used. The microneedle patch also maybe folded together after its use or placed back into its packaging(i.e., placed back in its tray) for disposal. Alternatively, themicroneedle patch and/or its packaging may be configured to be torn orotherwise partially or fully separated into multiple pieces followingadministration.

Manufacture

Methods for manufacturing microneedle patches and systems also areprovided. Such methods preferably are performed under a minimum ISO 7(class 10,000) process or an ISO 5 (class 100) process.

In one embodiment, the manufacture of solid, dissolvable microneedlesincludes filling a negative mold of the one or more microneedles with anaqueous or non-aqueous casting solution of the substance of interest anddrying the casting solution to provide the one or more solidmicroneedles. In other embodiments, other solvent or solventless systemsmay be used. Non-limiting examples of methods for filling the negativemold include deposition, coating, printing, spraying, and microfillingtechniques. The casting solution may be dried at ambient temperature fora period from about 30 minutes to about one week to form the dry solidmicroneedles (e.g., from about 45 minutes to about one week, from aboutone hour to about one week, from about one hour to about one day, etc.).

Alternatively, the casting solution may be vacuum-filled or filled intothe mold using a combination of non-vacuum filling and vacuum-filling.For example, in an embodiment the negative mold comprises a non-porousbut gas-permeable material (e.g., PDMS) through which a backside vacuumcan be applied. Although the negative mold is solid, it was determinedthat a sufficient vacuum could be applied through the backside when themolds are formed of such materials. In some embodiments, the backsidevacuum may be used alone or in combination with a positive pressureapplied on top of the mold. Such embodiments could advantageously reducethe time required and improve the accuracy and completeness when fillingthe mold with casting solution. For example, the casting solution may bevacuum-filled using a backside vacuum for a period from about 3 minutesto about 6 hours, from about 3 minutes to about 3 hours, from about 3minutes to about 1 hour, or from about 3 minutes to about 30 minutes.

Although various temperatures and humidity levels can be employed to drythe casting solution, the formulations preferably are dried attemperature from about 1° C. to about 150° C. (e.g., from about 5° C. toabout 99° C., from about 15° C. to about 45° C., from about 25° C. toabout 45° C., or at about ambient temperature) and about 0 to about 20%relative humidity.

In some embodiments, it may be desirable to use a multi-step castingprocess to form the microneedles and base substrate. For example, thetips of the microneedles may be partially filled in a first step with acasting solution comprising the substance of interest followed by one ormore subsequent fill steps with casting solutions of bulking polymerswith or without the same or a different substance of interest. Afterfilling and at least partially drying the microneedles in the negativemold, the adhesive layer and backing layer may be applied to the basesubstrate prior to removing the microneedles from the mold. In someembodiments, the adhesive layer and/or backing layer are pre-formedprior to application to the base substrate, while in other embodimentsthe adhesive layer and/or backing layer may be formed directly in-line.The patch may optionally also include an indicator and/or a separate tabportion incorporated into the patch.

After at least partially drying the microneedles, the microneedles maybe removed from the mold. For example, the microneedles may be removedfrom the mold before fully dry (e.g., when still in a rubbery state),but when strong enough to be peeled, and then dried further once removedfrom the mold to further solidify/harden the microneedles. Such atechnique may be useful when carboxymethylcellulose sodium, polyvinylalcohol, sugars, and other materials are used as a bulking polymer(matrix material) in the microneedles. In such embodiments, themicroneedles may complete drying prior to or after packaging.

The microneedle patches may then be attached to the trays and undergoone or more additional packaging steps. For example, the microneedlepatches may be applied to the tray and packed in a foil pouch withdesiccant, preferably under aseptic conditions. The foil pouchescontaining the microneedle patches and trays may then be removed fromthe aceptic conditions to be further packaged in cardboard boxes priorto being stored. The storage conditions will depend in part on thethermal stability of the substance of interest. For example, themicroneedle patches may require storage under refrigeration, for exampleat temperatures from about 2° C. to about 8° C.; in a freezer, forexample at temperatures below 0° C.; at ambient temperature; or atuncontrolled temperature, for example up to 50° C. The storage may befor the shelf life of the product or for a period less than the shelflife of the product.

Although the above process is described with reference to manufacturinga single microneedle patch, the negative molds may be configured to forma plurality of microneedle patches. For example, in embodiments thenegative mold may be configured to produce 6 or more patches, 12 or morepatches, and the like.

The microneedle patches, systems, and methods may be further understoodwith the following non-limiting examples.

Example 1: Fabrication of Microneedle Patches with Mechanical ForceIndicator

Etched, stainless steel microneedles were mounted on adhesive foambacking (TM9942, MacTac, Stow, Ohio) and packaged with polyacetal. Eachpatch contained 50 hexagonally-packed microneedles, 750 μm long, with arow spacing and column spacing of 1.6 and 1.0 mm, respectively. Partswere assembled with double sided adhesive (1522, 3M, Minneapolis, Minn.)and sent for ethylene oxide sterilization.

A mechanical force indicator was fabricated to facilitate microneedleinsertion. A resistive strain gauge load cell (RSP1-010M-A, LoadstarSensors, Fremont, Calif.) was used to evaluate these devices compared tothe force an experienced, blinded investigator uses to insertmicroneedle patches. The mechanical force indicators were constructedfrom polypropylene screw caps (91620A200, McMaster-Carr, Atlanta, Ga.),cardstock paper, and double-sided tape (1522, 3M, Minneapolis, Minn.).Tape was applied to the cardstock paper, cut into 14 mm circles, andapplied to the bottom of the device. The paper was applied to cover ahole that exists in the caps to ensure that even force was appliedacross the bottom of the device.

A study was carried out to evaluate use of the mechanical forceindicators. The mechanical force indicators were packaged separatelyfrom the patches, and the indicators were applied to patches duringadministration procedures. First, a patch would be placed on a humanparticipant's arm with the microneedles facing down. The adhesive wouldhold the patch in place. Then, the participant would take a mechanicalforce indicator from the investigator and place a device over themicroneedle array. The participant would then press the hinged lidclosed while keeping the device positioned over the needle array. Whenthe mechanical force indicator closed and made a clicking noise, theparticipant would throw the device away.

The participants in the study were given the following verbalinstructions for use of the patch with the mechanical force indicator:

-   -   Open the pouch. Peel away the blue plastic film. Pick up the        patch without touching the metal part (i.e., the microneedles).    -   Peel the foam part off the hard plastic part (i.e., the        microneedle patch packaging).    -   Put the patch on your arm. Place it metal side down on a part of        your forearm with the least amount of hair.    -   Place the mechanical force indicator directly above the metal        part of the patch.    -   Clinch your fist. Keep the mechanical force indicator in place        and press it closed until you hear a clicking noise.

The volume of the clicking noise was measured. At a distance of 15.2 cm,the closing snap produced a sound intensity of 71±1.2 dB (n=6, SoundMeter v.1.5.4 for Android devices, Smart Tools Co.). This isapproximately 12 times louder than normal conversation, 60 dB. At 45 cm,which is a better approximation of the distance from ear to volarforearm, the sound intensity should be approximately 62 dB, since soundintensity dissipates by the ratio of distances squared.

The study determined if participants could apply microneedle patcheswith minimal training. Subjects self-administered placebo microneedlepatches three times, had a placebo microneedle patch administered bystudy personnel and received an IM injection of saline in randomizedorder. Participants were well distributed in terms physical andsocioeconomic factors. The microneedle patch with the mechanical forceindicator made a snapping sound when a force of approximately 37 N wasapplied.

The results of the study were analyzed. Without the mechanical forceindicator, the median number of insertion sites of microneedlespuncturing into the skin observed on the first attempt by subjects toself-administer was 90%. The variability between participants was highwith an interquartile range (IQR) of 44%. On the second and thirdattempt, the median number of insertion sites observed increased to 94%and the variability decreased (IQR: 13-15%). The improvement inadministration success was statistically significant (p=0.003, n=57,Friedman's rank test), indicating a learning curve. This suggested theneed for a device to assist with microneedle insertion.

With the mechanical force indicator, the median number of insertionsites observed on the first attempt was 96%, and the variability betweensubjects was lower than before (IQR: 5%). The improvement in the numberof insertion sites observed on the first attempt was statisticallysignificant (p=0.006, Mann-Whitney U). The second and third attemptsperformed similarly well (median percent inserted: 93-95%, IQR: 9-10%).This shows that a mechanical force indicator that provides feedback tothe user regarding insertion force improved microneedle insertionsuccess.

While the invention has been described in detail with respect tospecific embodiments thereof, it will be appreciated that those skilledin the art, upon attaining an understanding of the foregoing, mayreadily conceive of alterations to, variations of, and equivalents tothese embodiments. Accordingly, the scope of the present inventionshould be assessed as that of the appended claims and any equivalentsthereof.

We claim:
 1. A microneedle patch comprising: a base substrate having amicroneedle side and an opposing back side; an array of dissolvablemicroneedles extending from the microneedle side of the base substrate,wherein the microneedles are molded of a composition which comprises (i)a substance of interest selected from active pharmaceutical ingredients,allergens, vitamins, cosmetic agents, cosmeceuticals, and markers, and(ii) a water-soluble matrix material in which the substance of interestis dispersed, wherein the water soluble matrix material comprisescarboxymethylcellulose sodium, polyvinyl alcohol, and/or a sugar; and anindicator connected to the opposing back side of the base substrate,wherein the indicator is configured to provide audible, tactile, andvisual signals when a force applied to the patch by a user, in thecourse of manually applying the patch to a person's skin to insert themicroneedles into the skin, meets or exceeds a predetermined threshold.2. The patch of claim 1, further comprising: a handle layer affixed tothe base substrate and including an elongated tab portion extendinglaterally away from a side of the microneedles, the tab portion beingconfigured for manual manipulation of the patch; and an adhesive layerdisposed between and securing together the base substrate and the handlelayer.
 3. The patch of claim 1, further comprising: a handle layeraffixed to the base substrate and including an elongated tab portionextending laterally away from the microneedles, the tab portion beingconfigured for manual manipulation of the patch; and an adhesive layerwhich comprises (i) a first adhesive composition disposed between andsecuring together the base substrate and the handle layer, and (ii) asecond adhesive composition disposed on the handle layer beyond the basesubstrate and configured to releasably secure the patch to the skin. 4.The patch of claim 3, wherein the first adhesive composition has acoefficient of adhesion between the base substrate and the handle layerthat is greater than the coefficient of adhesion of the second adhesivecomposition between the handle layer and a patient's skin.
 5. The patchof claim 1, wherein the indicator comprises a mechanical force indicatorwhich comprises a button that is displaced during application of theforce to the patch meets or exceeds the predetermined threshold.
 6. Thepatch of claim 5, wherein the mechanical force indicator comprises asnap dome disposed inside a housing.
 7. The patch of claim 6, whereinthe mechanical force indicator is integrated with another component suchthat the displacement is irreversible when the force applied to thepatch meets or exceeds the predetermined threshold.
 8. The patch ofclaim 7, wherein the another component comprises a snap-in-placemechanism or latch.
 9. The patch of claim 1, wherein the substance ofinterest comprises a vaccine or other active pharmaceutical ingredient.10. The patch of claim 1, wherein the microneedles have a height between100 μm to and 2000 μm.
 11. A microneedle patch comprising: a basesubstrate having a microneedle side and an opposing back side; an arrayof microneedles extending from the microneedle side of the basesubstrate, the microneedles being formed by molding a composition whichcomprises a substance of interest selected from active pharmaceuticalingredients, allergens, vitamins, cosmetic agents, cosmeceuticals, andmarkers; a handle layer affixed to the base substrate and comprising atab portion which extends laterally away from the microneedles andpermits a person to manually hold the tab portion to manipulate thepatch without contacting the microneedles; and an adhesive layerdisposed between and securing together the base substrate and the handlelayer, wherein the adhesive layer comprises a differential adhesive. 12.The patch of claim 11, wherein the adhesive layer has a coefficient ofadhesion between the base substrate and the handle layer that is greaterthan the coefficient of adhesion between the handle layer a patient'sskin.
 13. The patch of claim 11, wherein the substance of interestcomprises a vaccine or other active pharmaceutical ingredient.
 14. Thepatch of claim 11, further comprising an indicator connected to theopposing back side of the base substrate, wherein the indicator isconfigured to provide audible, tactile, and visual signals when a forceapplied to the patch by a user, in the course of manually applying thepatch to a person's skin to insert the microneedles into the skin, meetsor exceeds a predetermined threshold.
 15. The patch of claim 11, whereinthe microneedles are dissolvable microneedles and the compositionfurther comprises a water-soluble matrix material in which the substanceof interest is dispersed.
 16. The patch of claim 15, wherein the watersoluble matrix material comprises carboxymethylcellulose sodium,polyvinyl alcohol, and/or a sugar.
 17. A microneedle patch comprising: abase substrate having a microneedle side and an opposing back side; anarray of dissolvable microneedles extending from the microneedle side ofthe base substrate, the microneedles being formed molding and comprisinga composition which comprises a substance of interest selected fromactive pharmaceutical ingredients, allergens, vitamins, cosmetic agents,cosmeceuticals, and markers; a handle layer affixed to the basesubstrate and comprising a tab portion which extends laterally away fromthe microneedles and permits a person to manually hold the tab portionto manipulate the patch without contacting the microneedles; an adhesivelayer disposed between and securing together the base substrate and thehandle layer; and an indicator connected to the opposing back side ofthe base substrate, wherein the indicator is configured to provide avisual signal indicative of (i) at least substantially completeinsertion of the microneedles into the biological tissue, or (ii)completion of delivery of the substance of interest to the biologicaltissue, wherein the indicator comprises (a) a dye that is configured tobe transferred from the patch to the biological tissue, or (b) areactant that undergoes a chemical reaction producing a color change.18. The patch of claim 17, wherein the indicator comprises the dye andthe dye is disposed on the microneedle side of the base substrate or isdisposed in or coated onto at least part of the microneedles.
 19. Thepatch of claim 17, wherein the indicator comprises the reactant and thechemical reaction is configured to be triggered (i) upon removal of themicroneedle patch from its packaging and exposure, resulting from saidremoval, of the reactant to oxygen in air, (ii) upon insertion of themicroneedles into skin and exposure, resulting from said insertion, ofthe reactant to water from the skin, or (iii) upon removal of a releaseliner or other component of the patch before or after application of thepatch to the skin and exposure, resulting from said removal, of thereactant to air or light.
 20. The patch of claim 19, wherein thechemical reaction has a reaction time that is equal to or longer than apredetermined patch wear time.
 21. The patch of claim 17, wherein thesubstance of interest comprises a vaccine or other active pharmaceuticalingredient.